Biocidal compositions containing quaternary ammonium phenates and methods of use



United States Patent 3,417,184 BIOCIDAL COMPOSITIONS CONTAININGQUATERNARY AMMONIUM PHENATES AND METHODS OF USE Reginald L. Wakeman,Philadelphia, Pa., and Joseph F. Coates, Washington, D.C., assignors toMillmaster Onyx Corporation, Jersey City, NJ., a corporation of New YorkNo Drawing. Continuation-impart of application Ser. No. 292,764, July 3,1963. This application Oct. 18, 1966, Ser. No. 587,415

9 Claims. (Cl. 424-258) ABSTRACT OF THE DISCLOSURE A method andcompositions for external biocidal use, such as in shampoos and thelike, which utilizes an effective amount of a quaternary ammoniumphenate having the chemical structure:

wherein R is an alkyl having 8 to 18 carbon atoms, and X is a residue ofeither phenol or substituted pthenol whose only acidic group is at leastone hydroxyl group, the water solubility of the quaternary ammoniumphenate being no greater than 3 parts by weight per 100 parts by Weightof solution at room temperature.

This invention relates to cosmetic compositions containing quaternaryammonium compounds therein, and it more particularly relates to suchcompositions wherein the quaternary ammonium compounds are N-alkylisoquinolinium phenates or substituted phenates.

This is a continuation-in-part of co-pending application Ser. No.292,764, filed July 3, 1963, now US. Patent 3,285,923 of Nov. 15, 1966.

The quaternary ammonium compounds suitable for use in the presentcompositions contain as the anionic portions any monohydric orpolyhydric phenol which is free from carboxyl groups or sulfonic acidgroups. The phenol may have one or more benzene rings or it may havecondensed ring systems. Examples of such phenols are phenol itself; theisomeric cresols; xylenols; catechols; catechol ethers; resorcinols andalkylated resorcinols, such as hexyl resorcinol and phloroglucinol;isopropyl phenols; t butyl phenols; 4-methyl-6-t-butyl phenol;di-t-butyl-p-cresol; higher alkyl phenols such, for example, as octylphenol and nonyl phenol, o-phenyl phenol, p-phenyl phenol, 2,2-methylene bis-4-ethyl-6-t-butyl phenol; derivatives of the foregoingcompounds free from carboxyl and sulfonic acid groups; the various halophenols; halo cresols; halo xylenols; halo catechols; and their analogsand homologs', methoxy phenols and higher alkoxy phenols together withcorresponding alkylated homologs; amino phenols; bromo phenols and theircorresponding methyl, polymethyl and alkyl homologs; nitro phenols,nitro cresols, nitro xylenols, esters of phenolic acids such asparacarbomethoxy phenol, paracarboethoxy phenol, paracarbo-butoxyphenol, and paraca'rbobenzoxy phenol; naphthol and the chloro naphthols,al-kl naphthols, amino naphthols and the like; hydroxy diphenyl, hydroxydiphenyl ether, hydroxy diphenylene oxide, 2,2'-dihydroxy-5,5'-dichlorodiphenyl methane salicylaldehyde, and the like. In general, any phenoliccompound may be employed which is free from carboxylic and sulfonic acidgroups.

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The phenates are preferably prepared from their watersoluble salts suchas their sodium, potassium or ammonium salts, or in the form of the freephenol if solubility relationships permit.

Quaternary ammonium compounds useful in this invention are higher alkylisoquinolinium halides corresponding to the formula:

wherein X is a halogen atom such as bromine or chlorine, or a hydroxylgroup and R is an alkyl radical having from 8 to 18 carbon atoms,preferably having 12 to 16 carbon atoms. Typical examples are laurylisoquinolinium chloride, bromide or hydroxide, the correspondingmyristyl and cetyl compounds, or mixtures thereof.

These compounds have a low water solubility generally not in excess of 3parts by weight per parts of solution at room temperatures, so that theyare especially useful in applications wherein the known water-solublequaternary ammonium compounds are washed away or are physicallyincompatible or unsatisfactory because of their .high water-solubility.It is, of course, possible to promote water-solubility by the use ofsuitable solvents, coupling agents or dispersing agents. Furthermore,when an excess of either quaternary or phenolic compound is employed,the resultant compound may be soluble in aqueous solutions of the excessreactant.

The compounds may be prepared by mixing aqueous solutions of thequaternary ammonium salts with any of the aforementioned phenols, theiranalogs or homologs, or with a salt thereof. In the case of polyhydricphenols such, for example, as resorcinol, phloroglucinol or phrogallol,they may be employed in the form of their completely neutralized saltsor in any desired degree of neutralization, i.e., mono, di, trisodiumsalts or the like.

After thoroughly mixing, the organic product layer is separated from theaqueous layer (as with a separatory funnel) since two distinct phasesare formed. Separation may be facilitated by the addition of an organicsolvent immiscible with water. The product layer may be washed withwater to remove any residual by-product salt or unreacted materials. Thesolvent, if any, may be evaporated and the product air or "vacuum driedto a paste, wax, oil or solid.

It is not necessary to use an aqueous medium. Any solvent or solventmixture in Which the starting materials are soluble will besatisfactory. Non-aqeuous solvents facilitate the separation ofby-product inorganic salt and reduce the need for vacuum drying to getan anhydrous product. When a non-aqueous medium is employed, it isusually necessary to add a small amount of water to facilitate ionicreaction.

The product may be used, if desired, without drying since any entrappedwater is irrelevant to the microbiological activity of the compounds. Inother applications, removal of water may be essential for reasons notrelated to biological activity.

The products of this invention are particularly useful in that theyprovide a single chemical compound which has a broad spectrum ofmi-crobiocidal activity, ai'finity and substantivity for hair and scalpwhich can be used for treatment of dermatological disorders of the scalpsuch, for example, as dandruff, In vitro tests show them to beespecially active with respect to Pityrospo'rum ovale.

The microbiological activity of our compounds has been evaluated formicrobiological stasis by the Standard Tube Dilution Test, the techniquefor which is common knowledge to those skilled in the art. A Difco BactoCSMA Broth #0826 was used in the study. This test is used to determinethe lowest concentration of microbiologioally active compounds whichwill inhibit the growth of the organism in question. For wide range ofapplications, the inhibition of growth rather than outright kill issatisfactory.

Briefly put, the Tube Dilution Test consists in placing 9 cc. of theCSMA Broth in a test tube which is then sterilized in an autoclave. Onecc. solution of the microbiologically active compound at an appropriateconcentration is added to the test tube which is then inoculated with0.1 cc. of a twenty-four hour old culture of the organism under study.The test tube is then incubated at 37 C. for forty-eight hours andobserved for bacterial growth.

The same procedure is followed for fungi. In such tests, however, thetubes are incubated for fourteen days as a temperature suitable foroptimum fungal growth, usually 25 C.

The invention is illustrated by, but not restricted to, the followingexamples:

EXAMPLE I A stock solution containing 10 weight percent of sodiumpentachlorophene was prepared. An aliquot of the solution containing0.030 equivalents of sodium pentachlorophenol was vigorously agitatedwhile a chemically equivalent amount of a commercial grade of laurylisoquinolinium bromide (Onyx Chemical Company; Isothan Q75) in the formof a 10 weight percent solution was slowly added. The mixture was thenpoured into a separatory funnel. The mixture separated into two phases.The organic product layer was removed and vacuum dried to yield a darkbrown paste in 83% yield. The product was lauryl isoquinoliniumpentachlorophenate.

EXAMPLE II A solution was prepared containing 10 weight percent of thesodium salt of chloro o-phenyl phenol. To a vigorously agitated aliquotof this solution containing 0.044 equivalent weights of the compound wasadded a chemically equivalent amount of a 10% solution of laurylisoquinolinium bromide. The mixture was poured into a separatory funneland shaken, after which it was allowed to stand until it separated intotwo phases The organic product layer, a brown oil, was drawn off andvacuum dried to yield a brown paste of lauryl isoquinolinium chloroo-phenyl phenate in 90 yield.

If desired, an equivalent amount of lauryl isoquinolinium chloride maybe used instead of the bromide in the preceding examples.

EXAMPLE III Using techniques similar to that described in Example II,lauryl isoquinolinium compounds were obtained from the sodium salts oftetrachlorophenol, p-chloro m-cresol, p-chloro m-xylenol and from thedisodium salts of hexachlorobisphenol and dichlorobisphenol. Yields were93%, 88%, 89%, 90% and 70% respectively.

In place of lauryl isoquinolinium in the foregoing examples, we mayemploy equivalent amounts of octyl or decyl isoquinolinium chloride orbromide; equivalent amounts of myristyl, cetyl or stearyl isoquinoliniumchloride or bromide, and mixtures thereof.

These compounds, along with those of Examples I and II, are listed inTable I. This table shows their microbiological activity as well astheir solubility in water. This microbiological activity was determinedby the Standard Tube Dilution Test, described previously, using threedifferent organisms, i.e., Staphylococcus aureus, Salmonella typlzosaand Aspergillus niger. All of the products were found to bemicrobiologically active with respect to these three organisms.

TABLE I.-PROPERTIES OF THE REACTION PRODUCTS OF SODIUM SALTS OF VARIOUSOHLORINATED PHENOLS WITH LAYRYL ISOQUINOLINIUM BROMIDE Reciprocal ofStatic Water Dilution of Product vs. Chlorinated Phenol Solubility(g,/100 g.Sol) S. a. S. t. A. n.

Pcntachlorophenol 0. 07 10 10 10 'Ietrachlorophenol 0. 06 10 10 10Chloro o-phenyl phenol 0.009 10 10 10 Hexachlorobisphenol 0. 02 10 10 10Dichlorobisphenol 0. 07 10 10 l0 EXAMPLE IV The product formed accordingto Example III by reaction of lauryl isoquinolinium bromide with thesodium salt of p-chloro-m-cresol and having a solubility of 0.03 partper 100 grams of water at room temperature was evaluated against threedifferent fungi by the previously described Standard Tube Dilution Test,the following concentrations being found to be the effective staticdilution levels:

Asperillus niger:1/75,000 Penicillium luteum:1/75,000 Pullulariapullulans:1/75,000

Similar static levels were found for the analogous product derived fromthe reaction of lauryl isoquinolinium bromide with the sodium salt ofp-chloro-m-xylenol prepared by the method of Example III.

EXAMPLE V To a solution of 20 grams of the sodium salt ofparacarbomethoxy-benzoate in 200 cc. of water was added, with stiring, achemically equivalent amount of a 50% aqueous solution of laurylisoquinolinium bromide.

The mixture was allowed to stand in a separatory funnel until itseparated into two distinct layers. The lauryl isoquinolinium methylp-hydroxy benzoate formed the lower layer. This lower layer wasseparated and vacuum dried to yield a dark brown paste in 88.3% yield.

In a similar way, paracarboalkoxy phenates wherein the alkoxy is ethoxy,propoxy, butoxy and benzoxy, were reacted with lauryl isoquinoliniumbromide. The respective yields were 76%, 71% and 79%. All were darkbrown pastes.

EXAMPLE VII A solution of 14 grams of the sodium salt of o-phenyl phenolin 250 cc. of water was prepared and mixed with 250 cc. of a 10%solution of lauryl isoquinolinium bromide. Two layers formed. The lowerlayer contained the lauryl isoquinolinium o-phenyl phenate. This layerwas separated and vacuum dried to yield 18 grams of a solid brownproduct. This represented a 47% yield.

In a similar way the sodium salt of p-phenyl phenol gave a 45% yield ofa brown paste when reacted with lauryl isoquinolinium bromide.

The sodium salt of p-cresol gave a 98% yield of a dark red paste whenreacted with lauryl isoquinolinium bromide.

The sodium salt of phenol when reacted in aqueous solution with achemically equivalent amount of lauryl isoquinolinium bromide gave ayield of a dark red paste.

5 EXAMPLE vur To 70 cc. of a 10% aqueous solution of laurylisoquinolinium bromide in a 250 cc. separatory funnel was added 100 cc.of a 10% solution of the sodium salt of ditertiary .butyl p-cresol.These solutions were well mixed by vigorously shaking the separatoryfunnel. On standing, a dark red oil separated and formed the lowerlayer. This lower layer was drawn off into an evaporating dish andvacuum dried to give an 80% yield of lauryl isoquinolinium ditertiarybutyl p-cresylate, a dark brown paste. The di(lauryl isoquinolinium)salt of bisphenol was also prepared.

EXAMPLE IX To a 2.5% aqueous solution of the sodium salt of 4,4 thio bis(6-tertiary butyl o-cresol) was added a chemically equivalent amount ofa 10% aqueous solution of lauryl isoquinolinium bromide. On standing, ared oil precipitated to form a separate lower layer. This lower layerwas dried to give a 71.5% yield of lauryl isoquinolinum 4,4 thio bis(6-tertiary butyl o-cresylate).

EXAMPLE X To 60 cc. of a 10% aqueous solution of the sodium salt ofmixed tertiary butyl phenols was added 134 cc. of a 10% aqueous solutionof lauryl isoquinolinium bromide. The product layer was separated anddried to give a 76% yield of a lauryl isoquinolinium tertiary butylphenolate, a dark red paste.

In a similar way aqueous solutions of the sodium salts of 2,2 methylenebis(4-methyl-6-tertiary butyl phenol) and 2,2 methylene bis(4-ethyl-6-tertiary butyl phenol) were reacted with laurylisoquinolinium bromide to give essentially water insoluble salts inyields of 99% and 91%, respectively. The lauryl isoquinolinium salt of2,6 ditertiary butyl alpha dimethyl amino phenol was also prepared.

EXAMPLE XI To a solution of 14 grams of the solution salt ofsalicylaldehyde in 200 cc. of water was added, with stirring, 379 cc. ofa 10% solution of lauryl isoquinolinium bromide. The mixture was allowedto stand and two distinct layers formed. The product layer containingthe lauryl isoquinolinium salt of salicylaldehyde was a red-brown oilwith a density greater than water. It was separated and vacuum dried toyield a red paste in 79% yield.

EXAMPLE XII Using standard bacteriological methods described above, theproducts described in Examples V through XI were tested againstStaphylococcus aureus, Salmonella typhosa and Aspergillus niger forbiostasis, referred to respectively as S.a., S.t., and A.n. in thefollowing table. Results of these tests are shown in the following TableII.

TABLE II Reciprocal of Static Dilution Lauryl Isoquinolim'um ReactionProduct With of Product vs.

S. a. S. t. A. n.

Nonyl phenol 10 10 Para carbo methoxy phenol 10 10 Para carbo ethoxyphenol. 10 10 Para carbo propoxy phenoL 10 10 Para carbo butoxy phenoL10 10 Para carbo benzoxy phenol" 10 10 o-Phenyl phenol 10 10 p-Phenylphenol- 10 10 p-CresoL. 10 10 Phenol 10 10 Di-t-Butyl -Cresol 10 10 4,4thio bis(6t-Butyl o-Cresol) 10 10 10 Mixed t-Butyl phenols 10 10 10 2,6di-t-Butyl alpha dimethyl amino para cresol 10 10 10 2,2 methylene bis(l-methyl fi't-Butyl phenol) 10 10 10 2,2 methylene bis (at-ethylt-G-butyl phenol) 10 10 10 Salieylaldehyde I 10 10 10 10 Bis phenol 6EXAMPLE x111 A stock shampoo formulation was prepared as follows:

1 Percent Triethanolamine salt of lauryl sulfate 30 Laurie aciddiethanolamine condensate 8 Ethoxylated lanolin 2 Water 60 A secondsolution was prepared of 20% by weight of lauryl isoquinolinium p-chlorom-xylenate in isopropanol.

This isopropanol solution was mixed with the stock shampoo formulationto give a finished product which contained 0.1 weight percent of laurylisoquinolinium p chloro m-xylenate. The finished product is a clear,red, slightly viscous foamy liquid which was found effective for thecontrol of dandruff. Any of the higher alkyl isoquinolinium phenolicderivatives listed in the preceding examples having microbiologicallyactive properties may be used in sufficiently active amounts in place ofthe above Xylenate compound.

It is possible to formulate shampoo preparations by directly adding thedesired lauryl isoquinolinium halide, for example, lauryl isoquinoliniumbromide, together with a selected phenolic compound, such as p-chloromxylenol or mixtures thereof, to the shampoo formulation.

The super amide was melted and was then added to the remainingingredients which were then mixed at room temperature to provide thefinal product.

EXAMPLE XV A hair cream-rinse was prepared as follows:

Percent Polyethylene glycol 200 monostearate 3 Lauryl isoquinoliniumparacresylate 1-4 Water to make 100%.

The monostearate was melted and was then mixed at [room temperature withthe remaining ingredients to form the final product.

EXAMPLE XVI A liquid germicidal hand-cleaning soap was preparedaccording to the basic formula for Medicinal Soft Soap presented on page646 of the Sixteenth Revision of the Pharmacopeia of the United Statesof America.

650 grams of the soap paste was dissolved in 200 grams of alcohol plus20 grams of oil of lavender with agitation until it became homogeneous.

10 grams of lauryl isoquinolinium nonyl phenate was dissolved in gramsof alcohol. This was added to the soap solution until the tincture washomogeneous. After aging for twenty-four hours, the solution wasclarified by filtration, and adjusted to make grams by the addition ofalcohol.

This was used as a pre-surgical hand-scrubbing soap, and was tested assuch by the Price Technique for Determining Degermation of the Skin asdescribed in Antiseptics, Disinfectants, Fungicides, and Chemical andPhysical Sterilization edited by George F. Reddish (Lea and Febiger,1957) pages 101-102. It was found to be equal to or better than a soapcontaining 2% of hexachlorophene.

7 EXAMPLE xvrr A foot powder was prepared by coating kaolin with 0.11%lauryl isoquinolinium phenate from an ethyl al cohol solution. Thecoated material was then dried and 10% thereof mixed with 90% talc.

It is to be understood that all the aforementioned percentages are byWeight unless otherwise stated.

Examples XIII, XIV, XV and XVI disclose specific foaming, detergent andsolubilizing agents. However, this is only for the purpose ofillustration, it being understood that any feasible agents of thesetypes can be used within the scope of the present invention.

Obviously, many modifications of the present invention are possible inthe light of the above teachings. It is, therefore, to be understoodthat within the scope of the appended claims, the invention may bepracticed otherwise than as specifically described.

The invention claimed is:

1. A biocidal method of treating human living tissue which comprisesexternally applying to said tissue a biocidally elTective amount of aquaternary ammonium phenate having the structure:

wherein R is an alkyl having 8 to 18 carbon atoms, and X is a residue ofa member of the group consisting of phenol and substituted phenol whoseonly acidic group is at least one hydroxyl group, the water solubilityof said quaternary ammonium phenate being not greater than 3 parts byweight per 100 parts of solution at room temperature.

2. The method of claim 1 wherein the phenate is applied to the hair.

3. The method of claim 1 wherein the phenate is applied to a foot.

4. The method of claim 1 wherein the phenate is applied in a liquidcarrier.

5. The method of claim 1 wherein the phenate is applied as a powder.

6. A hair shampoo consisting essentially of a liquid carrier and abiocidally efiFective amount of a quaternary ammonium phenate have thestructure:

wherein R is an alkyl having 8 to 18 carbon atoms, and X is a residue ofa member of the group consisting of phenol and substituted phenol whoseacidic group is at least one hydroxyl group, the water solubility ofsaid quaternary ammonium phenate being not greater than 3 parts byweight per parts of solution at room temperature.

7. The shampoo of claim 6 wherein the liquid carrier contains aneffective amount of a detergent and foaming agent.

8. The shampoo of claim 6 wherein the liquid carrier contains anefiective amount of a solubilizer for the quaternary ammonium phenate.

9. A skin-treating powder consisting essentially of a biocidallyeffective amount of a quaternary ammonium phenate having the structure:

wherein R is an alkyl having 8 to 18 carbon atoms, and X is a residue ofa member of the group consisting of phenol and substituted phenol whoseonly acidic group is at least one hydroxyl group, the water solubilityof said quaternary ammonium phenate being not greater than 3 parts byweight per 100 parts of solution at room temperature mixed with a solidpulverulent carrier.

References Cited UNITED STATES PATENTS 2,223,142 11/1940 Weirich l67--582,250,480 7/1941 Gump 260-619 2,255,694 9/1941 Beale 16758 2,524,73810/1950 Snell 167-58 2,668,136 2/1954 Winkle 167-58 2,783,279 2/1957Chiddix 260--6l9 2,961,375 11/1960 Shaw 167-58 FOREIGN PATENTS 809,6552/1959 Great Britain. 809,689 3/1959 Great Britain.

ALBERT T. MEYERS, Primary Examiner.

V. C. CLARKE, Assistant Examiner.

U.S. C1. X.R.

